Apoptosis signal‐regulating kinase (ASK) 1 is activated in response to various cytotoxic stresses including TNF, Fas and reactive oxygen species (ROS) such as H 2 O 2 , and activates c‐Jun NH 2 ‐terminal kinase (JNK) and p38. However, the roles of JNK and p38 signaling pathways during apoptosis have been controversial. Here we show that by deleting ASK1 in mice, TNF‐ and H 2 O 2 ‐induced sustained activations of JNK and p38 are lost in ASK1 −/− embryonic fibroblasts, and that ASK1 −/− cells are resistant to TNF‐ and H 2 O 2 ‐induced apoptosis. TNF‐ but not Fas‐induced apoptosis requires ROS‐dependent activation of ASK1–JNK/p38 pathways. Thus, ASK1 is selectively required for TNF‐ and oxidative stress‐induced sustained activations of JNK/p38 and apoptosis.

ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis